Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties. While neural progenitor cells (NPCs) are crucial for proper brain development, it is unclear whether they play a role in BPD-associated neurodevelopmental deficits. Here, we show that hyperoxia-induced experimental BPD in newborn mice led to lifelong impairments in cerebrovascular structure and function as well as impairments in NPC self-renewal and neurogenesis. A neurosphere assay utilizing nonhuman primate preterm baboon NPCs confirmed impairment in NPC function. Moreover, gene expression profiling revealed that genes involved in cell proliferation, angiogenesis, vascular autoregulation, neuronal formation, and neurotransmission were dysregulated following neonatal hyperoxia. These impairments were associated with motor and cognitive decline in aging hyperoxia-exposed mice, reminiscent of deficits observed in patients with BPD. Together, our findings establish a relationship between BPD and abnormal neurodevelopmental outcomes and identify molecular and cellular players of neonatal brain injury that persist throughout adulthood that may be targeted for early intervention to aid this vulnerable patient population.
Marissa A. Lithopoulos, Xavier Toussay, Shumei Zhong, Liqun Xu, Shamimunisa B. Mustafa, Julie Ouellette, Moises Freitas-Andrade, Cesar H. Comin, Hayam A. Bassam, Adam N. Baker, Yiren Sun, Michael Wakem, Alvaro G. Moreira, Cynthia L. Blanco, Arul Vadivel, Catherine Tsilfidis, Steven R. Seidner, Ruth S. Slack, Diane C. Lagace, Jing Wang, Baptiste Lacoste, Bernard Thébaud
GO enrichment analysis of SVZ tissue from 12-month-old mice reveals that early life hyperoxia exposure leads to long-term transcriptional changes involved in many biological processes, including vascular autoregulation, brain development, and neurotransmission.